In this section, we highlight the key high-impact studies, updates, and analyses published in medicine during the past week.
Goal-Directed Resuscitation for Patients with Early Septic Shock
The monumental Rivers et al publication laid forth the groundwork for early goal-directed therapy (EGDT) for sepsis management, a framework that has been embraced by the Surviving Sepsis Campaign. Newer evidence suggests that not all of the parts of EGDT may be necessary for achieving optimal outcomes. In this large multicenter randomized controlled trial conducted at 51 centers, 1600 patients with sepsis and refractory hypotension or hypoperfusion were randomly assigned to either EGDT or usual care. The usual-care group was managed without strict adherence to EGDT protocols and was prohibited from using SccO2 measurements during the 6-hour intervention period. Investigators founds that patients in the EGDT group received larger volumes of IV fluids in the first 6 hours when compared to the usual-care group (mean +/- SD, 1964 +/-1415 ml vs. 1713 +/- 1401 ml, p< 0.001) and also were more likely to receive vasopressors (66.6% vs. 57.8%), blood transfusions (13.6% vs. 7.0%, p< 0.001) and dobutamine (15.4% vs. 2.6%, p< 0.001). After 90 days, the EGDT group had an 18.6% mortality rate vs. 18.8% in the usual-care group (absolute risk difference EGDT vs. usual-care: -0.3%, 95% CI: -4.1 – 3.6, p = 0.90). There was also no statistically significant difference in survival time, length of hospital stay, duration of organ support, or survival time. This study therefore suggests that adhering strictly to EGDT, which may result in more IV fluids, vasopressors, and transfusions, does not appear to results in better outcomes for patients with sepsis and refractory hypotension or hypoperfusion.
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Synthetically engineered T-cells that can target specific lymphocyte markers such as CD19 are a new strategy for treatment of relapsed and refractory acute lymphoblastic leukemia (ALL). In this pilot clinical trial, 25 children aged 5 to 22 years old and 5 older patients aged 26 to 60 years with refractory or relapsed ALL received infusions of T-cells targeting CD19, called CTL019. Investigators found that after infusion, the CTL019 cells were able to proliferate in vivo and be found in the blood, bone marrow, and cerebrospinal fluid. 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 patients status post stem-cell transplantation, achieved complete disease remission with sustained 6-month event-free survival in 67% of patients (95% CI: 51-88) and overall survival rate of 78% (95% CI: 65-95). With regards to side effects, all patients experienced cytokine-release syndrome with severe symptoms in 27% of patients. However, this was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. This study therefore demonstrates that a chimeric antigen receptor-modified T cell therapy targeting CD19 appears effective in achieving sustained disease remission in patients with refractory or relapsed ALL.
Association Between Hospital-Level Obstetric Quality Indicators and Maternal and Neonatal Morbidity
Several obstetric-specific quality measures are monitored and publically reported as part of an effort to improve the quality of obstetric care. There has yet to be analysis as to the varying degrees of quality that exist in and their actual effects on obstetric outcomes. In this observational study, investigators looked at 115,742 deliveries that occurred in 2010 in New York City hospitals. The two quality indicators that were considered were elective, nonmedically indicated deliveries between 37 and 39 weeks of gestation and cesarian delivery performed in low-risk mothers. This study found that these quality indicators varied widely. Rates of elective deliveries performed between 37 and 39 weeks of gestation varied from 15.5 to 41.9 per 100 deliveries. Rates of cesarean sections in low-risk mother had a wide range from 11.7 to 39.3 sections per 100 deliveries. Obstetric outcomes were similarly quite different with maternal morbidity ranging from 0.9 to 5.7 mothers with complications per 100 deliveries and 3.1 to 21.3 neonates with complications per 100 births. Interestingly, investigators found no significant association between the quality indicators, early elective deliveries and cesarean section in low-risk mothers, and maternal morbidity (RR 1.00, 95% CI: 0.98-1.2 and RR 0.9, 95% CI: 0.96-1.01 respectively) or neonatal morbidity (RR 0.99, 95% CI: 0.97-1.01 and RR 1.01, 95% CI: 0.99-1.03 respectively). This study therefore demonstrates that while quality indicators and obstetric outcome indicators varied widely across New York City hospitals, there was no association between the former and the latter, thereby putting into question the utility of the currently reported obstetric quality measures.
Carotid endarterectomy has been the standard treatment for symptomatic internal carotid stenosis. Carotid stenting emerged as an alternative but was shown in previous randomized trials to be associated with a higher rate of procedure-related strokes, mostly in elderly patients, but lower rates of myocardial infarction, cranial nerve palsy, and access site hematoma. A follow-up review of this data suggested that most of the strokes in these trials were non-disabling and that there may actually be no difference in rates of major stroke or death between endarterectomy and stenting. In this large randomized clinical trial, the International Carotid Stenting Study, 1713 patients older than 40 years with symptomatic carotid stenosis were randomly assigned to treatment with stenting or endarterectomy and were then followed for a median of 4.2 years. Investigators found that although the number of overall strokes was more frequent in the stenting group than in the endarterectomy group (15.2% vs. 9.4% at 5 years by intention-to-treat analysis, HR: 1.71, 95% CI: 1.28-2.30, p < 0.001), the number of fatal or disabling strokes did not differ significantly (6.4% vs. 6.5%, HR: 1.06, 95% CI: 0.72-1.57, p = 0.77). Similarly the distribution of modified Rankin scale scores, a standardized measurement for functional outcomes, did not differ significantly at 1 year, 5 years, or final follow-up. This study therefore shows that endarterectomy for symptomatic internal carotid stenosis may not significantly reduce the long-term risk of major stroke and subsequent functional disability when compared to carotid stenting.
Human embryonic stem cells (hESCs) have held promise for replacing human tissue. However, the long-term safety of regenerative medicine with hESCs, given their capacity for self-renewal and implications for potential tumor formation, immune rejection, and formation of unwanted cell types, has yet to be fully understood. In this study, investigators analyzed the safety outcome at a median of 22 months from transplantation in two different prospective phase I and II studies involving the subretinal transplantation of hESC-derived retinal pigment epithelium in 9 patients with Stargardt’s macular dystrophy and 9 patinets with atrophic age-related macular degeneration. Researchers found that 13 of 18 (72%) of patients showed increasing subretinal pigmentation after transplant, which resulted in significantly improved visual acuity and vision-related quality-of-life measures. There was no evidence of unwanted adverse effects, including uncontrolled proliferation, rejection, or other complications. This study therefore provides the first evidence that hSCs can be used effectively to produce sustaining grafts with little to no adverse effects related to cell pluripotency.
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